Central Insulin Administration Improves Whole-Body Insulin Sensitivity via Hypothalamus and Parasympathetic Outputs in Men

Abstract

Animal studies suggest that insulin action in the brain is involved in the regulation of peripheral insulin sensitivity. Whether this holds true in humans is unknown. Using intranasal application of insulin to the human brain, we studied the impacts of brain insulin action on wholebody insulin sensitivity and the mechanisms involved in this process. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic glucose clamp before and after intranasal application of insulin and placebo in randomized order in lean and obese men. After insulin spray application in lean subjects, a higher glucose infusion rate was necessary to maintain euglycemia compared with placebo. Accordingly, clamp-derived insulin sensitivity index improved after insulin spray. In obese subjects, this insulin-sensitizing effect could not be detected. Change in the high-frequency band of heart rate variability, an estimate of parasympathetic output, correlated positively with change in whole-body insulin sensitivity after intranasal insulin. Improvement in whole-body insulin sensitivity correlated with the change in hypothalamic activity as assessed by functional magnetic resonance imaging. Intranasal insulin improves peripheral insulin sensitivity in lean but not in obese men. Furthermore, brain-derived peripheral insulin sensitization is associated with hypothalamic activity and parasympathetic outputs. Thus, the findings provide novel insights into the regulation of insulin sensitivity and the pathogenesis of insulin resistance in humans.

Selective Insulin Resistance in Homeostatic and Cognitive Control Brain Areas in Overweight and Obese Adults

“…Furthermore, this change in CBF probably contributes to the homeostatic control of whole-body metabolism (21). Concomitantly, we found in lean individuals that nasal insulin administration correlates with peripheral insulin sensitivity (7) and improves peripheral insulin sensitivity through hypothalamic and parasympathetic outputs in lean but not in obese men (22), providing further evidence that peripheral and central insulin sensitivity are highly linked processes. Additionally, the insulin-induced reduction in hypothalamic CBF in the current study correlates significantly with the amount of VAT independent of the individual's other fat compartments.…”

Central insulin‐like growth factor‐1 ( IGF ‐1) restores whole‐body insulin action in a model of age‐related insulin resistance and IGF ‐1 decline

“…In rodents, intranasal IGF‐1 has been shown to rapidly and effectively gain entry to the CNS via the olfactory and trigeminal system (Thorne et al ., 2004), and protect against Huntington disease and toxin‐induced brain injury (Cai et al ., 2011; Lopes et al ., 2014). Interestingly, intranasal insulin, which is under investigation in humans to treat metabolic (Heni et al ., 2014; Gancheva et al ., 2015) and cognitive decline (Claxton et al ., 2015), has shown promise in healthy volunteers, but efficacy appears to wane in obese (Heni et al ., 2014) and T2DM (Gancheva et al ., 2015) patients, which may be the direct result of acquired central insulin resistance in these subjects. Thus, it seems plausible that increasing IGF‐1 in the brain may represent an important therapeutic alternative to circumvent central insulin resistance for the treatment of these diseases in older humans, a possibility that should be considered in future clinical trials.…”

Central Regulation of Glucose Metabolism in Humans: Fact or Fiction?

“…The IN spray application transiently increases the insulin concentration in liquor (8), likely due to bulk flow within the perivascular space of cerebral blood vessels (9). Using this technique, evidence for the central insulin regulation of systemic lipolysis (10), modulation of liver fat content and hepatic energy metabolism (11), and improvement in whole-body insulin sensitivity (12) has been provided. Interestingly, effects of IN on EGP seem to depend on the experimental conditions with no changes in the fasting state (11) but with reduction during pancreatic clamps (13).…”

“…Modulation of energy-demanding processes might contribute to the rise in hepatic energy status after IN application. Of note, central insulin regulation of peripheral insulin sensitivity and hepatic energy metabolism was blunted in obese humans and patients with type 2 diabetes (11,12), suggesting that the presence of a combined central and peripheral IR and a dysregulation of a brain-liver cross talk in type 2 diabetes. Nevertheless, IN may have some limitations resulting from variable cerebral insulin delivery and/or peripheral insulin spillover.…”

“…Specifically, it will be interesting to find out which and how brain-derived signals, induced either by IN or diazoxide, reach peripheral tissues to modulate glucose and energy metabolism. The autonomic nervous system is also a good candidate to mediate these effects in humans (5,12). Animal data revealed that CNS insulininduced suppression of EGP depends on vagus nerve activation (6), whereas the sympathetic nervous system mediates for the reduction of adipose tissue lipolysis (2).…”